Carcinoma of the Breast PDF

CARCINOMA OF THE BREAST. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1046-1061. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pages...

CARCINOMA OF THE BREAST. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1046-1061. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pages 656-660. CASE PRESENTATION: GRETA GUSTAFSON. A 48-year-old woman was admitted with a lump in her left breast. She first noticed it two weeks ago while she was taking a shower. Physical examination revealed a nontender, slightly moveable, 2-cm mass in the upper outer quadrant of her left breast. A 1.5-cm moveable lymph node was observed in left axilla. A mammogram showed an irregular mass with mass with spiculated margins borders and stippled calcifications in the upper outer quadrant of the left breast. A core biopsy of the left mass showed a well-differentiated invasive ductal carcinoma and scirrhous type cancer of the breast (cT1cN1M0). Gross examination of the lumpectomy specimen showed a 2-cm, grey, scirrhous mass in the central portion of the specimen. The margins of the lumpectomy specimen were free of tumor. Serial sections of the left axillary lymph node revealed metastatic ductal carcinoma; thus, a completion axillary dissection is performed a week later, revealing two additional positive lymph nodes out of 15. Special studies reveal the tumor to be estrogen and progesterone receptor positive with a high proliferative rate and a diploid DNA histogram. The tumor is HER2 positive. The patient is given chemotherapy and radiotherapy. INTRODUCTION. Breast cancer is a heterogeneous disease regarding its clinical presentation, pathological classification and clinical course. At least 20 different histological breast cancer types are described by the WHO. Most tumors are derived from mammary ductal epithelium, mainly the terminal duct-lobular unit. Most recently, reclassification of breast cancer based on gene expression established a widely applied molecular classification of breast cancers distinguishing three major subtypes, luminal, basal-like, and 1 Her2+ breast cancers. This system correlates with prognosis better than the standard histological or receptor status designation. EPIDEMIOLOGY. In the United States, breast cancer is the most commonly diagnosed cancer in women, followed by lung cancer. Breast cancer is the second-leading cause of cancer deaths after lung cancer. The incidence rates increase sharply with age, with the highest incidence rates overall being in older women. The median age of diagnosis of breast cancer is 63. • Approximately 1% of breast cancers occur in males. ETIOPATHOGENESIS. 1. Hereditary breast cancer. The major risk factors for the development of breast cancer are hormonal (estrogen) and genetic. Breast carcinomas can therefore be divided into sporadic cases, probably related to hormonal exposure, and hereditary cases, associated with germline mutations. • Overall, 10% of all breast cancers are associated with inherited genetic mutations. Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are the most common causes of hereditary breast cancer, responsible for 80-90% of cases. Germline mutations in BRCA1 and BRCA2 confer high risk of breast and ovarian cancers. The penetrance of these genes is incomplete. BRCA1 and BRCA2 are tumor suppressors that have normal roles in DNA repair in many tissues. Both BRCA1 and BRCA2 are components of a large complex of proteins that are required to repair double-stranded DNA breaks through a process called homologous recombination. • Other tumor suppressor genes associated with germline mutations that convey a high risk for breast cancer, as part of well-described syndromes, include TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), STK11 (Peutz-Jeghers syndrome), CDH1 (hereditary diffuse gastric cancer syndrome), and PALPB2. 2. Sporadic breast cancer. In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare event. Three main genetic pathways resulting in different types of breast carcinoma have been identified. • The most common pathway is characterized by mutations in the PIK3CA gene and leads to luminal (ERpositive) carcinomas. PIK3CA gene encodes phosphoinositide-3 kinase (PI3K), an important component of signaling pathways downstream of growth factor receptors • The second pathway consists of HER2-positive cancers. HER2 (also known as ERBB2) is a receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis by stimulating the RAS- and PI3KAKT signaling pathways. The only common molecular mechanism for HER2 overexpression is gene amplification, found in >95% of HER2-positive carcinomas. • The third pathway is characterized by mutations in the CDH1 gene, encoding E-cadherin, a transmembrane protein that forms adherens junctions to bind cells within tissues and play important roles in cell adhesion. Due to loss of E-cadherin, invasive lobular carcinomas are discohesive and often fail to incite a desmoplastic response. 3. Risk factors of sporadic breast cancer. Only 25% of sporadic breast cancers have risk factors identified by epidemiologic studies. These risk factors are listed below. (A) Gender. Breast cancer occurs 100 times more frequently in women than in men. (B) Age. The incidence rises throughout a woman's lifetime, peaking at the 70-80 years age group and then declining slightly thereafter. (C) BMI: A higher BMI in the postmenopausal period is associated with a higher risk of breast cancer. (D) Tall stature. Increased height is associated with a higher risk of breast cancer. (E) Benign breast disease. Proliferative breast disease especially with atypia are associated with an increased risk of breast cancer. 2 (F) Hormonal factors. Higher endogenous estrogen levels are associated with higher breast cancer risk. Combined estrogen/progesterone replacement in postmenopausal women has been shown to increase risk of subsequent breast cancer. Oral contraceptive usage is associated with an increased risk. (G) Earlier menarche or later menopause. Both are associated with a higher breast cancer risk. Cumulative lifetime exposure to estrogen determines the level of this risk. (H) Nulliparity. Nulliparous women are at higher risk for breast cancer compared with parous women (I) Increasing age at first full-term pregnancy. Women who become pregnant later in life have an increased risk of breast cancer. (J) Family history. Breast cancer risk is higher if a woman has a first degree relative with breast cancer. (K) Alcohol use, smoking. Smoking and alcohol consumption is associated with a higher risk. (L) Mammographic breast density. Patients with denser breasts have a higher breast cancer risk. HISTOPATHOLOGICAL CLASSIFICATION. Breast cancer can be broadly categorized into in situ carcinoma and invasive (infiltrating) carcinoma. • Breast carcinoma in situ is further sub-classified as either ductal or lobular; growth patterns and cytological features form the basis to distinguish between the two types. Ductal carcinoma in situ (DCIS) is considerably more common than its lobular carcinoma in situ (LCIS) counterpart. • Similar to in situ carcinomas, invasive carcinomas are a heterogeneous group of tumors differentiated into histological subtypes. The major invasive tumor types include ductal carcinoma, lobular carcinoma, and special histologic types of mucinous (colloid), tubular, medullary, and papillary carcinomas. Of these, infiltrating ductal carcinoma is, by far, the most common subtype accounting for 70–85% of all invasive lesions. Ductal carcinoma and lobular carcinomas originate from the luminal or basal cells of the terminal ductlobular unit. Only papillary carcinomas and Paget disease of the breast originate within the major lactiferous ducts. CARCINOMA IN SITU. Carcinoma in situ refers to the presence of apparently malignant epithelial cells that have not penetrated the basement membrane. These lesions are obligate precursors of invasive carcinoma. 1. Ductal carcinoma in situ (DCIS). DCIS consists of a malignant population of cells limited to ducts and lobules by the basement membrane. Malignant looking cells spread throughout ducts and lobules and unfold the terminal duct lobular unit resulting in a dilated structure. If the diameter of the dilated structure exceeds 2 mm in diameter, the lesion qualifies as DCIS. • Microscopically, there are five architectural subtypes: ◦ Comedocarcinoma. Ducts are filled with very large, atypical cells that have abundant eosinophilic cytoplasm and irregular nuclei. Central necrosis is a prominent factor. The necrotic debris undergoes dystrophic calcification. There is stromal inflammation and fibrosis present around the affected ducts. 3 ◦ Cribriform variant consists of proliferation of a uniform population of cells forming a sieve-like arrangement. Secondary lumens are rounded. The nuclei are evenly distributed. Mitotic figures are rare. ◦ Micropapillary variant features epithelial tufts with no fibrovascular cores projecting into the lumen. ◦ Papillary variant is characterized by delicate fibrovascular cores lined by tall columnar cells extending into the duct lumen. ◦ Solid variant is characterized by proliferating cell that completely fill and distort the duct lumen. • DCIS doesn't typically have any signs or symptoms. DCIS is a nonpalpable lesion recognized only by abnormalities seen in mammogram (small clusters of calcifications that have irregular shapes and sizes). 2. Lobular carcinoma in situ (LCIS). LCIS involves terminal duct lobular unit filling and expanding acini but not the terminal duct. Proliferating cells are monomorphic, evenly spaced, slightly larger than normal, with indistinct cell borders and pale cytoplasm. They have uniform small nuclei with evenly distributed chromatin. LCIS does not show nuclear pleomorphism, mitosis, or necrosis. • There are no specific clinical features. LCIS by itself does not cause any grossly visible or palpable alteration in breast tissue. INVASIVE CARCINOMA. Invasive ductal carcinoma accounts for 76% of breast cancers whereas the remainder is categorized as histological ‘special types’. Invasive ductal carcinoma is called 'no special type' (NST) because the cancer cells have no histologic features that class them as a special type of breast cancer. 1. Invasive ductal carcinoma, no special type. (A) Gross findings. These tumors are typically hard, gray-white, gritty masses that invade the surrounding tissue in a haphazard fashion to create the characteristic irregular, stellate shape mass that radiates into the surrounding tissue. There is a characteristic grating sound when the tumor is cut or scraped; grossly there are small foci of calcification on the cut surface; the hard, gray to white areas correspond to desmoplastic stromal response; these areas are the basis for the term “scirrhous” derived from the Greek word for “hard”. (B) Microscopic findings. The tumor is characterized by the presence of tubules or glands with visible lumens admixed with solid cords and nests of tumor cells lacking lumens. The cytological features range from bland to highly malignant. Tumor cells induce a fibrosclerotic response as they infiltrate the breast parenchyma, and this reaction is, in large part, responsible for the clinically and grossly palpable mass, the radiologic density, and ultrasound characteristics of typical invasive ductal carcinomas. Stroma is fibroblastic with scattered inflammatory cells. DCIS is present in most cases. (C) Grading. Infiltrating ductal carcinomas are divided into three grades based on tubule formation and mitotic rate. When the tumor is composed of tubule formation in >70% of the tumor mass it is considered grade 1 (well-differentiated). When the tumor is composed of tubule formation in 10–75% of 4 the tumor mass, it is considered grade 2 (moderately differentiated). Grade 3 tumors show tubular formation in <10% of the tumor mass. 2. Special histologic types of invasive breast carcinoma. These types are important to recognize because of their specific clinical associations. (A) Lobular carcinoma. Invasive lobular carcinoma is the second most common type of invasive breast cancer. Some invasive lobular carcinomas have a macroscopic appearance identical to that of invasive ductal carcinomas. However, in many cases no mass lesion is grossly evident. On light microscopy, lobular carcinoma is reveals discohesive epithelial cells of low nuclear grade, without the formation of tubules, nests, sheets or clusters. Small tumor cells insidiously infiltrate the mammary stroma and adipose tissue individually and in a single file pattern. They often grow in a target-like configuration around the normal mammary ducts. When cells form small cords with only one cell in width, it is called “arrangement in Indian files”. PAS stain identifies mucus in intracytoplasmic lumens. • Furthermore, lobular carcinoma is not as frequently associated with desmoplastic response in the adjacent stroma as ductal carcinoma. (B) Tubular carcinoma. This histological type is characterized by small, minimally branched, round, wellformed tubular structures with gaping lumens infiltrating the stroma. Myoepithelial cells are absent on immunohistochemical stains. Tubular carcinoma is a well-differentiated tumor: tumor cells are cytologically low grade and metastases are rare. (C) Mucinous (colloid) carcinoma. This type is characterized by small clusters of uniform, round cells with minimal amounts of cytoplasm floating in abundant lakes of mucus. Grossly the tumor displays a gelatinous appearance. 5 (D) Medullary carcinoma. Medullary carcinoma forms solid syncytium-like sheets of large cells with vesicular nuclei containing prominent nucleoli and frequent mitoses. The connective tissue stroma is negligible. The tumor border is pushing, noninfiltrative. There is a moderate lympho-plasmacytic infiltrate in the stroma. Lymph node metastases are infrequent. PATTERNS OF SPREAD. The axillary lymph nodes are the primary group responsible for lymphatic drainage in the breast and, consequently, are the most common location for breast cancer metastasis. However, lymphatic pathways running from the breast, via intercostal spaces, to parasternal lymph vessels have also been identified. According to the American Joint Committee on Cancer (AJCC) regional lymph node metastasis normally travels to the ipsilateral axillary, supraclavicular, subclavicular, and internal mammary lymph nodes. • Distant metastatic spread is common in breast cancer. The incidence of metastasis is higher in patients with positive axillary lymph nodes. Bone is the most common primary site of distant metastasis. Breast cancer is not regarded as a single entity but as a heterogeneous disease with different biological subtypes. Bone metastases are more frequent primary site of metastasis in luminal A subtypes. Liver metastases were formed mostly by the luminal HER2 overexpressing subtype, and lung metastases were formed mostly by triple negative subtype. MOLECULAR CLASSIFICATION. The current system of histological classification does not reflect accurately the biological complexity of breast cancers. In addition to the conventional use of microscopic type, grade and immunohistochemical analysis of hormone receptors, molecular profiling has also been used to characterize breast cancers. • Pathological analysis of breast cancer biopsy determines the hormone receptor status. The large majority of breast cancers are estrogen receptor-positive (ER-positive, ER+) and/or progesterone receptor-positive (PR-positive, PR+). Some breast cancers express HER2 receptors. A smaller percentage of breast cancers do not express hormone receptors. • Molecular classification of breast carcinomas has significant therapeutic and prognostic consequences. There are three molecular subtypes: 1. Luminal subtypes. The luminal subtypes are characterized as luminal A and luminal B. They are the most common subtypes of breast cancer and make up most ER-positive breast cancers. The name “luminal” derives from similarity in gene expression between these tumors and the epithelium lining the mammary ducts. They typically express cytokeratins 8 and 18. They are characterized by expression of ER, PR, and other genes associated with ER activation. Because tumors of both groups are ER-positive, they respond to hormonal therapy, including estrogen receptor blockers such as tamoxifen, selective estrogen receptor modulators, and aromatase inhibitors. (A) Luminal A tumors. Luminal A tumors make up about 40% of all breast cancers. They are ER+, PR+, and HER2‒. They have high expression of ER-related genes, low expression of the HER2 cluster of genes, and low expression of Ki-67. The Ki-67 protein is a cellular marker for proliferation. Morphologically, most luminal A tumors are well differentiated carcinomas of no special type, tubular carcinomas, lobular carcinomas, and mucinous carcinomas. Luminal A tumors show a tumor grade of 1 or 2 and carry the best prognosis of all breast cancer subtypes, with high survival rates and low recurrence rates. (B) Luminal B tumors. Luminal B tumors account for 20% of all breast cancers. They tend to be ERpositive. They have relatively lower expression of ER-related genes. They also tend to be PR positive or negative. PR is a prognostic factor: loss of PR suggests a more aggressive behavior and less response to hormonal therapy. ER+/PR‒ tumors represent a distinct subset of breast cancer with aggressive features and poor outcome despite being clinically ER+. They also tend to be HER2-negative; only 30% of 6 luminal B tumors present an overexpression of HER2. They have higher expression of Ki-67. ERpositive/PR-positive/HER2-positive tumors are also called triple positive tumors. These tumors show a lower level of ER expression, a lower level of or negative PR expression, and a higher level of Ki-67 labeling. Compared to luminal A tumors, luminal B tumors tend to have higher tumor grade, larger tumor size and higher lymph node positivity. Luminal B tumors carry a worse prognosis than luminal A tumors. Morphologically, this group of tumors is less well differentiated and consists mostly of invasive ductal carcinomas of no special type, and also some invasive micropapillary carcinomas. 2. HER2-enriched. The HER2-enriched subtype makes up about 10% to 15% of breast cancers. HER2 gene encodes a transmembrane tyrosine kinase receptor that binds to its extracellular signals and initiates a signaling cascade mediating cell proliferation. HER2 gene amplification results in aggressive tumor growth and poor clinical outcome. HER2-enriched tumors do not express genes that define the luminal and basal-like subtypes. Although most HER2 type tumors are HER2+ about 30% are HER2‒. These tumors ted to be ER‒, PR‒, have higher tumor grade and lymph node positivity. These tumors often express androgen receptor. HER2-enriched breast cancers that are HER2-positive can be treated with anti-HER2 receptor antagonists such as trastuzumab. 3. Basal-like. As the name suggests, tumors of this subtype express genes typical of normal myoepithelial basal cells of the breast. Basal like cancers account for 10% -20% of breast cancers and are more prevalent among patients of African, African American, and Latino descent. Most of these tumors fall under the category of triple-negative breast cancers because they are ER, PR, and HER2 negative. Basal-like carcinomas may represent tumors that arise because of inherited predilection for carcinogenesis. Most BRCA-1-mutated cancers are basal-like. Triple-negative breast cancer is more commonly diagnosed in women younger than 40 years compared with hormone-positive breast cancer. These tumors are of high histologic grade and have a very high mitotic index. The most common histology is infiltrating ductal carcinoma, although a rare histologic subtype, medullary carcinoma, is generally triple negative. Triple-negative breast cancer tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes, there are no approved targeted treatments available, other than the administration of chemotherapy. 4. Correlation between histological and molecular subtypes. The invasive ductal carcinoma and invasive lobular carcinoma are composed of tumors in all molecular categories. CLINICAL PRESENTATION. Invasive carcinoma almost always presents as a palpable mass. The “classic” features of invasive breast carcinoma include a hard, immovable, single dominant lesion with irregular borders. Palpable tumors are associated with axillary lymph node metastases in over 50% of patients. When the tumor involves the central portion of the breast, retraction of the nipple may develop. • Lymphatics may become so involved as to block the local area of skin drainage and cause lymphedema 7 and thickening of the skin. In such cases, tethering of the skin to the breast by Cooper ligaments mimics the appearance of an orange peel, an appearance referred to as peau d'orange. • The term inflammatory carcinoma is reserved for tumors that present with a swollen, erythematous breast. This gross appearance is caused by extensive invasion and obstruction of dermal lymphatics by tumor cells. The underlying carcinoma is usually diffusely infiltrative and does not form a discrete palpable mass. This can result in confusion with true inflammatory conditions and a delay in diagnosis. IMAGING STUDIES. In countries with established breast cancer screening programs, most patients present due to an abnormal mammogram. Mammographically detected cancers are smaller and without local or distant metastases. • Invasive breast carcinoma is associated with a wide range of mammographic patterns. In one study, 58% of breast cancer patients had a mammographic mass, 44% had clustered microcalcifications, 23% had both a mass and microcalcifications on the mammogram and 8% had architectural distortion of dense tissue without an obvious mass. In addition, 12% of the tumors were invisible on mammography. • A mammographic mass most often appears as mass with irregular spiculated margins borders, and less often as an irregularly outlined but non-spiculated mass. ◦ Clustered microcalcifications are calcium particles of various size and shape measuring between 0.1 to 1 mm in diameter and numbering more than four to five per cubic centimeter. Histologically, these represent intraductal calcifications in areas of necrotic tumor. ◦ Linear branching microcalcifications are most associated with the comedocarcinoma. ◦ The architectural distortion corresponds to straight lines in a radial pattern. • Up to 1/3 of cases show no abnormality on mammographic examination. INTRODUCTION. Paget disease of the breast (PBD) is a rare form of breast cancer that is characterized by proliferation of malignant glandular epithelial cells (in situ carcinoma) in the nipple areolar epidermis. Disease is named after the pathologist and surgeon Sir James Paget, who published his findings of a relationship between a nipple rash and mammary gland tumors in 1874. PDB accounts for only 1-3% of new cases of female breast cancer. The presenting age ranges from 24 to 84 years with average age at diagnosis of 57 years. 8 PATHOLOGY. PBD is a manifestation of breast carcinoma. It does not constitute an independent disease. The Paget cell arise from an underlying mammary adenocarcinoma, with the neoplastic ductal epithelial cells migrating through the ductal system of the breast into the epidermis of the nipple. • The histologic hallmark of PDB is the presence of malignant, intraepithelial adenocarcinoma cells occurring singly or in small groups within the epidermis of the nipple and/or areola. Paget cells are large cells with abundant pale cytoplasm and large nuclei with prominent nucleoli in the surface epithelium that tend to form clusters in the basal portions. They are larger than keratinocytes, and have pale, abundant cytoplasm. The clear appearance of cytoplasm Paget cells is due to their abundant content of mucus. With PAS, Paget cell’s cytoplasm assumes a purple-magenta color. Up to 90% of cases of PDB overexpress HER2. HER2 overexpression in PDB likely explains the worse prognosis reported for invasive breast cancer with Paget disease. CLINICAL PRESENTATION. The hallmark of PDB is a scaly, raw, vesicular, or ulcerated lesion that begins on the nipple and then spreads to the areola. PDB is usually unilateral, although bilateral cases have been described. Pain, burning, and/or pruritus are commonly associated with PDB. About 50% of patients have a palpable mass in the underlying breast tissue. INTRODUCTION. Breast cancer is an uncommon disease in men; it accounts for approximately 1% of all breast cancers. The mean age at diagnosis is 67 years, in comparison with 63 years for Caucasian women. ETIOLOGY. Risk factors are similar to those in women and include increasing age, first-degree relatives with breast cancer, exposure to exogenous estrogens or ionizing radiation, alcohol consumption, infertility, obesity, prior benign breast disease, and Klinefelter syndrome. • Approximately 20% of men with breast cancer have a family history of the disease. Inherited mutations in BRCA also increase the risk of breast cancer in men, although the risk appears to be higher with inherited BRCA2 rather than BRCA1 mutations. CLINICAL PRESENTATION. Most men with breast cancer generally present with a painless, firm mass. Because breast epithelium in men is limited to large ducts near the nipple, carcinomas usually present as a palpable subareolar mass 2 to 3 cm in size and/or as nipple discharge. 9 • Dissemination follows the same pattern as in women. Axillary lymph node involvement is present in about half of cases at the time of diagnosis, and distant metastases to the lungs, brain, bone, and liver are common. PATHOLOGY. Approximately 90% of breast cancers in men are invasive ductal carcinomas. In contrast, invasive lobular carcinomas account for 1.5% of cases. The most common molecular subtype of breast cancer in men is ER-positive. HER2-enriched and triple-negative breast cancers account for 15% and 4% respectively 10